Treatment of intestinal dysbiosis with immunoglobin

ABSTRACT

A process is provided for inhibiting symptoms of intestinal dysbiosis in a subject that includes the oral administration to the subject suffering from intestinal dysbiosis an IgA, IgM, or a combination thereof. When administered in a therapeutic quantity based on the subject characteristics and the type of IgA or IgM, symptoms of intestinal dysbiosis in that subject are inhibited. Even non-secretory forms of IgA or IgM are effective when administered orally.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 15/205,359 filed Jul. 8, 2016, which in turn is a continuationof U.S. patent application Ser. No. 15/014,200 filed Feb. 3, 2016, nowU.S. Pat. No. 9,409,996 which in turn is a continuation of U.S. patentapplication Ser. No. 14/264,053 filed Apr. 28, 2014, now U.S. Pat. No.9,273,129, which in turn is a continuation of U.S. patent applicationSer. No. 13/214,952 filed Aug. 22, 2011, now U.S. Pat. No. 8,709,413,that in turn is a continuation-in-part of U.S. patent application Ser.No. 12/138,758 filed Jun. 13, 2008, now U.S. Pat. No. 8,021,645; whichin turn is a continuation-in-part of U.S. patent application Ser. No.11/851,606 filed Sep. 7, 2007, now U.S. Pat. No. 7,794,721; which inturn is a continuation-in-part of U.S. patent application Ser. No.11/839,781 filed Aug. 16, 2007, now U.S. Pat. No. 7,597,891; which inturn is a continuation-in-part of U.S. patent application Ser. No.11/610,154 filed Dec. 13, 2006. The contents of these applications arehereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates in general to processes for the treatmentintestinal dysbiosis with orally administered immunoglobulin A (IgA),including secretory IgA, compositions administered in the form ofpharmaceutical compositions. Additionally this invention relates ingeneral to processes for the treatment of intestinal dysbiosis withorally administered immunoglobulin M (IgM), including secretory IgM,compositions administered in the form of pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Intestinal dysbiosis is the disturbance of the normal balance ofbacterial species in the intestine (Levy M et al 2017). Dysbiosis is adistinct microbial ecological state that is causally linked to themanifestation, diagnosis or treatment of a particular disease (Levy M etal 2017). This often is a consequence of the administration of broadspectrum antibiotics to treat infection (Yoon and Yoon 2018). Intestinaldysbiosis is also found in individuals with a deficiency of IgA in thesecretions of the intestinal tract (Fadlallah et al 2018). IntestinalIgA that adheres to intestinal bacteria facilities the symbioticrelationship between the bacteria and the host, such as a person(Nakajima et al 2018, Donaldson et al 2018). Food intolerance includes,but is not limited to, food protein enteropathy and food proteinenterocolitis/proctitis (G. Vighi, et al 2008, Caubet et al 2011).Irritable bowel syndrome is sometimes caused by food intolerance(Collins et al 2009). Symptoms of intestinal dysbiosis include

upset stomach.

nausea.

constipation.

diarrhea.

bloating.

The symptoms of irritable bowel syndrome can vary significantly fromperson to person. A partial listing of irritable bowel syndrome symptomsincludes:

Abdominal pain

Abdominal distention, bloating, gas, indigestion

Constipation

Diarrhea, chronic or occasional

Food allergy is most often attributed to IgE antibodies with antigenicspecificity for specific foods (Granato and Piguet 1986; Wang et al2010). Foods normally induce local intestinal mucosal production of IgAand IgM (Shimoda et al 1999). Food intolerance and allergy areassociated with deficiency in IgA (Walker et al 1999, Harrison et al1976). It has been hypothesized that food antigen IgA may competitivelybind to food antigens, and thereby protect the subject from reacting tothat food with an allergic response (Possin et al 2010). Food antigenspecific IgA is found in the blood plasma (Vojdani 2009, Trajkovski2008). Food allergy is associated with a relative decrease in foodantigen specific IgA in the intestines (Frossard C P at al 2004).Application of antigen-specific IgA to the respiratory mucosa in miceprevents increased airway hyperreactivity in allergic asthma (Schwarzeet al 1998; U.S. Pat. No. 5,670,626). Ulcerative colitis is a chronicinflammation of the large intestine. There is decreased mucosal IgA inthe intestinal mucosa of patients with ulcerative colitis (Cicalese etal 1995). Food antigen challenge in the presence of Staphylococcalenteroxin B has been shown to induce ulcerative colitis in a mousedisease model (Yang 2005). Non-IgE mediated food intolerance is alsoknown to exist and be most common in infants and young children due toingested dietary proteins such as those found in cow's milk and soyprotein creating profound discomfort. While non-IgE mediated foodallergy is rarely life threatening, it can cause significant morbidityin rapidly growing infants and young children. (Jyonouchi, 2008).

The prior art failed to explore orally administered IgAs or IgMs as apotential medicament for the treatment of food allergy and foodintolerance.

Thus, there exists a need for an IgA therapeutic or an IgM therapeuticfor the treatment of food allergy and food intolerance. There alsoexists a need to provide such a therapeutic in a dosing form well suitedfor treating an affected subject.

SUMMARY OF THE INVENTION

A process is provided for inhibiting symptoms of intestinal dysbiosis ina subject that includes the oral administration of an IgA or an IgM. tothe subject suffering from food allergy or food intolerance an IgA or anIgM. When administered in a therapeutic quantity based on the subjectcharacteristics and the type of IgA or IgM, symptoms of intestinaldysbiosis in that subject are inhibited. Even non-secretory forms of IgAand IgM are effective when administered orally. The administeredimmunoglobulin is readily formed from monoclonal or polyclonal sources.Recombinant forms of the immunoglobulins are also operative herein. Whenthe immunoglobulin is IgA, the IgA is readily administered in a dimeric,or polymeric form that optionally includes secretory component. When theimmunoglobulin is IgM, the IgM is readily administered in a pentamericform that optionally includes secretory component. Semisynthetic humansecretory IgA and semisynthetic human secretory IgM are not naturalsubstances in that they are comprised of a recombinant human secretorycomponent protein in addition to the immunoglobulin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention has utility as a treatment for intestinaldysbiosis. The process includes treatment with monoclonal- orpolyclonal-IgAs that are, dimeric or polymeric and/or secretory IgA;and/or monoclonal- or polyclonal-IgM that are, pentameric and/orsecretory IgM. While monomeric IgA is susceptible to gastrointestinaldegradation it has been surprisingly found that monomeric immunoglobulinmaintains some antibody function after oral administration (Kelly C etal 1997) Because of its resistance to degradation in thegastrointestinal tract, secretory IgA and secretory IgM are generallyeffective at lower doses. Immunoglobulins have minimal side effectsbecause they are naturally present in the gastrointestinal tract.Dimeric IgA and pentameric IgM according to the present invention may bebound to secretory component in order to mimic natural secretory IgA andnatural secretory IgM endogenous to the subject. Alternatively they maybe administered without bound secretory component.

As used herein, a “subject” is defined as a human.

As the present invention uses an immunoglobulin rather than a metabolicor immunological inhibitor, an effective treatment is provided whichdoes not disturb the body's metabolism.

The following description of the preferred embodiment(s) is merelyexemplary in nature and is in no way intended to limit the invention,its application, or uses.

IgA and IgM in various forms including polyclonal IgA that aremonomeric, dimeric or polymeric; and monoclonal- or polyclonal-IgM thatis secretory or pentameric are all known to the art, as evidenced forexample, by the references incorporated herein.

In one embodiment, the invention provides a process for medicaltreatment of humans involving the oral administration of secretory IgAwhich can be derived from a number of sources. One such source for theIgA is pooled human plasma following Cohn cold ethanol fractionation toproduce fraction III precipitate as performed by those of skill in theart of protein separation. The IgA byproduct is further purified byadsorption onto jackbean lectin (jacalin) or onto an ion exchange mediumin neutral or slightly acidic conditions as performed by those of skillin the art of protein purification. Another source for the IgA isrecombinant IgA produced from a hybridoma or a transgenic plant.

A more detailed description of isolation of an IgA component as abyproduct from pooled human plasma or hyperimmune pooled human plasma isas follows. Ethanol fractionation of pooled human plasma is a well-knownprocess to prepare immunoglobulin G. Pooled human plasma is firstobtained from licensed plasmapheresis centers in the United States andtested for various pathogens including the HIV virus. The firstmanufacturing step of most commercial immunoglobulin G preparationsinvolves a modified cold ethanol fractionation according to Cohn toproduce Cohn fraction II. In the fractionation process, many infectiousviruses are eliminated from the pooled human plasma. Followingfractionation, the Cohn fraction II is subjected to adsorption onto anion exchange medium. This step may selectively reduce the IgAconcentration to less than 0.1%. Such a step is important for producingimmunoglobulin G for intravenous infusion into humans. This is becausesome individuals undergo an anaphylactic-like reaction if treated withintravenous IgG that contains IgA as an impurity.

The modified cold ethanol fractionation process according to Cohn is aseries of fractionations using various levels of ethanol, pH, andtemperature to produce a fraction II which is further treated to produceimmunoglobulins as described above. In the fractionation method, pooledhuman plasma is first treated to produce a cryoprecipitate andcryo-supernatant. The cryo-supernatant is subjected to a first ethanolfractionation to yield a supernatant I. Supernatant I is subjected to asecond ethanol fractionation to yield fraction II+III. Fraction II+IIIis subjected to a third ethanol fractionation procedure to yield asupernatant III and Fraction III precipitate.

The fraction III precipitate enriched in IgA is generally discarded asan unwanted byproduct. According to the invention, this unwanted IgAfollowing ion exchange adsorption purification is further treated byincubation with immobilized hydrolases to inactivate viruses andvasoactive substances. Such treatment has been proven to eliminate manyviruses tested including HIV, Sindbis, and vaccinia. Other antiviraltreatments, as known to those skilled in the art, are used incombination and consist of solvent detergent processes, nanofiltrationand/or heat inactivation. Usually three antiviral steps are implemented.Following incubation to remove viruses, the concentration of the activematerial is adjusted with sterile saline or buffered solutions to ensurea constant amount of active material per milliliter of reconstitutedproduct. Finally, the solution with a constant amount of reconstitutedproduct is sterilized by filtration before use.

The ethanol fractionation process according to Cohn is well known in theart and is described in Cohn et al., J. Am. Chem. Soc. 1946; 68:459-475,Oncley et al., J. Am. Chem. Soc. 1949; 71:541-550, and in most detail inpages 576-602, Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 3,second edition (1963). Alternatively, ion exchange chromatography may beused to obtain the IgA byproduct including the dimeric and polymericforms during the manufacture of intravenous immunoglobulin. From 4% to22% of plasma IgA is dimeric and polymeric IgA (Delacroix et al. 1981;Delacroix et al. 1983). The resulting dimeric and polymeric IgA-J chainsare purified.

In a preferred embodiment, the compositions of the invention contain, inaddition to the IgA component, recombinant secretory component. Humansecretory component can be produced by recombinant techniques asdescribed in Crottet et al., Biochem. J. 1999; 341:299-306. Theresulting dimeric IgA is further coupled to recombinant secretorycomponent. In a preferred embodiment, the coupling is accomplished byforming disulfide bonds under mildly oxidizing conditions. (Jones 1998)Dimeric IgA containing both J chain and secretory component is againpurified by ion-exchange and size exclusion chromatography and/orultrafiltration as described in Lullau et al., J. Biol. Chem. 1996;271:16300-16309, Corthesy, Biochem. Soc. Trans. 1997; 25:471-475, andCrottet et al., Biochem. J. 1999; 341:299-306, as performed by those ofskill in the art of protein purification. Purified dimeric and polymericIgA containing secretory component is optionally stabilized for exampleby the addition of human serum albumin to a final concentration of 5%.The presence of the human J chains and secretory component in thecompositions of the invention leads to doses of immunoglobulin A whichare more physiologically effective than compositions without suchcomponents. These selected additives are natural ligands, detergents,salts, buffers, and chemicals that have been shown to increase thestability of proteins in vivo. It is appreciated that proteins are alsoreadily stabilized through the addition of a stabilizing agent. Theseagents illustratively include trehalose, glycine betaine, mannitol,L-arginine, L-glutamic acid, potassium citrate, CuCl₂, proline, xylitol,K₂PO₄, and combinations thereof (Leibly et al., Golovanov et al.).

In still other embodiments, an IgA or IgM is combined with a semi-solidor solid carrier can be further formulated into hard or soft shellgelatin capsules, tablets, or pills. In some embodiments, the hard orsoft shell gelatin capsules, tablets, or pills are enterically coated.Exemplary of such enteric coatings are those detailed in U.S. Pat. No.5,629,001.

In still other inventive embodiments, the IgA or IgM is combined with anantacid. Antacids operative herein illustratively include neutralizinghydroxyl group containing compounds, as well as H2 blockers of sodiumbicarbonate, magnesium oxide, magnesium hydroxide, calcium carbonate,magnesium trisilicate, magnesium carbonate, aluminum hydroxide gel,cimetidine, ranitidine or combinations thereof.

Dimeric IgA contains two IgA monomers plus J chain.

The secretory IgA antibodies may be administered alone as a liquid orsolid, preferably in a solid powder form and preferably in admixturewith a carrier to form a pharmaceutical composition such as a tablet,capsule or suppository.

Since preferred methods of administration are oral with solid oraldosage forms such as tablets and capsules being especially preferred, orenteric installation. These are prepared according to conventionalmethods known those skilled in the art. The secretory IgA antibodies mayalso be combined with other pharmaceutically acceptable carriers such asvarious liquids, proteins or oils which may also provide additionalnutritional and/or pharmaceutical benefits. Remington Science andPractice of Pharmacy, 20^(th) ed. (2000).

These compositions optionally contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample, sugars, sodium chloride, and the like. Prolonged residence inthe intestinal lumen of the IgA or IgM can be brought about by the useof agents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate, (e) solution retarders, as for example, paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol, and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art; as detailed, for example inU.S. Pat. Nos. 4,017,647; 4,385,078; 4,518,433; and 4,556,552.

They may contain opacifying agents, and can also be of such compositionthat they release the active compound or compounds in a certain part ofthe intestinal tract in a delayed manner. Examples of embeddingcompositions which can be used are polymeric substances and waxes. Theactive compounds can also be in microencapsulated form, if appropriate,with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil,glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acidesters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Since the effect of the IgA and IgM antibodies is dependent on theirreaching the small intestine, preferred tablets or capsules are entericcoated. Alternatively, the active IgA and IgM antibodies can themselvesbe microencapsulated prior to formulation. Preparation of microcapsulesof IgA and IgM antibody as well as preparation of enteric coated tabletsor capsules can be achieved by conventional methods as detailed above.

It is appreciated that the therapeutic amount of IgA or IgM depends onthe form thereof, with forms subject to gastrointestinal degradationrequiring larger doses. Typically amounts of IgA or IgM from about 0.005mg to 50 grams per day are used and preferably, 1 mg to 40 grams perday. Generally, secretory IgA or IgM are each independently effective asa treatment when provided to the patient at about 10 grams per day.Forms of IgA or IgM that are prone to gastrointestinal degradation aretypically effective in doses increased by at least 80% relative tosecretory forms. For example, about 5 grams of secretory IgA could begiven to a subject per day in a single dose or in divided doses 3 to 4times per day. Preferably, multiple doses are administered with mealslikely containing food allergens. It is appreciated that a physician canreadily adjust the doses of the IgA or IgM to be administered based onthe subject's response to treatment. Many factors are considered in doseadjustments. Dosages of secretory IgA or secretory IgM for adult humansenvisioned by the present invention and considered to be therapeuticallyeffective will range from between about 5 mg to 50 g. However, it is tobe understood that doses can readily be adjusted to provide appropriateamounts of the IgA antibody to any subject, including children.

The present invention also provides a process for medical treatment ofhumans involving the oral administration of monomeric IgA which can bederived from pooled human plasma or monoclonal IgA which can be derivedby hybridoma technology (B Cell Design, Limoge, France).

The present invention also provides a process for medical treatment ofhumans involving the oral administration of secretory IgM which can bederived from pooled human plasma following Cohn cold ethanolfractionation to produce fraction III precipitate as performed by thoseof skill in the art of protein separation as described above. IgMbyproduct is further purified by adsorption onto an ion exchange mediumin neutral or slightly acidic conditions as performed by those of skillin the art of protein purification. Another source for the IgM isrecombinant IgM produced from a hybridoma.

The invention is further described by reference to the followingdetailed examples, wherein the processologies are as described below.These examples are not meant to limit the scope of the invention thathas been set forth in the foregoing description. Variations within theconcepts of the invention are apparent to those skilled in the art.

Example 1

Monoclonal dimeric IgA is obtained from hybridoma technology. Themonoclonal IgA is stabilized by the addition of human serum albumin to afinal concentration of 5% and encapsulated. The final solution isadjusted to a therapeutic dose of 10 g IgA daily. The IgA isadministered to a person suffering with intestinal dysbiosis. One dayafter initiation of treatment, the intestinal dysbiosis suffererexperiences diminution of his/her symptoms.

Example 2

The process of Example 1 is repeated with the IgA administered with anenteric, encapsulating coating and a lower daily dose of 2 g to achievea similar result.

Example 3

The process of Examples 2 is repeated with monoclonal IgA replaced withpolyclonal IgA that is obtained from pooled human plasma following Cohncold ethanol fractionation to produce fraction III precipitate. IgA isfurther purified by adsorption onto an ion exchange medium in neutral orslightly acidic conditions. IgA-J chain dimers and polymers arepurified. IgA-J chain dimers and polymers are then further coupled torecombinant secretory component again by disulfide bonding in mildlyoxidizing conditions, preferably at a molar ratio of secretory componentto IgA-J chain dimers and polymers of 1:1. IgA containing both J chainand secretory component is again purified. Purified IgA containing Jchain and secretory component is stabilized by the addition of humanserum albumin to a final concentration of 5%. The final solution ofsecretory IgA is adjusted to a therapeutic dose of 5 mg IgA and isadministered to a person suffering with intestinal dysbiosis. One monthafter initiation of treatment the intestinal dysbiosis sufferer nolonger has any symptoms.

Example 4

The process of Example 4 is repeated with monoclonal IgA replaced withpolyclonal IgM that is obtained from pooled human plasma following Cohncold ethanol fractionation to produce fraction III precipitate. IgM isfurther purified by adsorption onto an ion exchange medium in neutral orslightly acidic conditions. IgM-J chain pentamers are purified. IgM-Jchain pentamers are then further coupled to recombinant secretorycomponent again by disulfide bonding in mildly oxidizing conditions,preferably at a molar ratio of secretory component to IgM-J chainpentamers of 1:1. IgA containing both J chain and secretory component isagain purified. Purified IgM containing J chain and secretory componentis stabilized by the addition of human serum albumin to a finalconcentration of 5%. The final solution is adjusted to a therapeuticdose of 10 g IgM. The IgM is administered to a person suffering withintestinal dysbiosis. One month after to initiation of treatment theintestinal dysbiosis sufferer no longer has symptoms.

Examples 5-9

Examples 5-9 are repeated with monoclonal IgA replaced with polyclonalIgM per Example 4 to achieve like results.

REFERENCES

-   Berzofsky J. A., Berkower I. J., Epstein S. L., Monoclonal    Antibodies in Chapter 12, Antigen-Antibody Interactions and    Monoclonal Antibodies, pp. 455-465 in Fundamental Immunology, Third    Edition, W. E. Paul (ed), Raven Press, N Y 1993. Berzofsky et al.,    Fundamental Immunology, Third Edition, 1993, pp 455-462.-   Cicalese L, Duerr R H, Nalesnik M A, Heeckt P F, Lee K K, Schraut    W H. Decreased mucosal IgA levelsin ileumof patients with chronic    ulcerative colitis. Dig Dis Sci. 1995 April; 40(4): 805-11.-   Cohn E. J., Strong L. E., Hughes W. L., Jr., Mulford D. J.,    Ashworth J. N., Melin M., Taylor H. L., Preparation and Properties    of Serum and Plasma Proteins IV. A System for the Separation into    Fractions of the Protein and Lipoprotein Components of Biological    Tissues and Fluids, J. Am. Chem. Soc. 1946; 68; 459-475.-   S. M. Collins, E. Denou, E. F. Verdu, P. Bercik. The putative role    of the intestinal microbiota in the irritable bowel syndrome.    Digestive and Liver Disease 41 (2009) 850-853-   Corthesy B., Recombinant Secretory IgA for Immune Intervention    Against Mucosal Pathogens, Biochem. Soc. Trans. 1997, 25; 471-475.-   Crottet P., Cottet S., Corthesy B., Expression, Purification and    Biochemical Characterization of Recombinant Murine Secretory    Component, A Novel Tool in Mucosal Immunology, Biochem. J. 1999,    341; 299-306.-   Caubet J C, Nowak-Wegrzyn A. Current understanding of the immune    mechanisms of food protein-induced enterocolitis syndrome. Expert    Rev Clin Immunol. 2011 May; 7(3):317-27.-   Delacroix D. L., Hodgson H. J., McPherson A., Dive C., Vaerman J. P.    Selective transport of polymeric immunoglobulin A in bile.    Quantitative relationships of monomeric and polymeric immunoglobulin    A, immunoglobulin M, and other proteins in serum, bile, and    saliva. J. Clin. Invest. 1982 August; 70(2):230-41-   Delacroix D. L., Elkom K. B., Geubel A. P., Hodgson H. F., Dive C.,    Vaerman J. P. Changes in size, subclass, and metabolic properties of    serum immunoglobulin A in liver diseases and in other diseases with    high serum immunoglobulin A. J. Clin. Invest. 1983 February;    71(2):358-67.-   Donaldson G P, Ladinsky M S, Yu K B, Sanders J G, Yoo B B, Chou W C,    Conner M E, Earl A M, Knight R, Bjorkman P J, Mazmanian S K Gut    microbiota utilize immunoglobulin A for mucosal colonization.    Science. 2018 May 18; 360(6390):795-800. doi:    10.1126/science.aaq0926. Epub 2018 May 3.-   Fadlallah J, El Kafsi H, Sterlin D, Juste C, Parizot C, Dorgham K,    Autaa G, Gouas D, Almeida M, Lepage P, Pons N, Le Chatelier E,    Levenez F, Kennedy S, Galleron N, de Barros J P, Malphettes M,    Galicier L, Boutboul D, Mathian A, Miyara M, Oksenhendler E, Amoura    Z, Dore J, Fieschi C, Ehrlich S D, Larsen M, Gorochov G. Microbial    ecology perturbation in human IgA deficiency. Sci Transl Med. 2018    May 2; 10 (439). pii: eaan1217. doi: 10.1126/scitranslmed.aan1217.-   Frossard C P, Hauser C, Eigenmann P A. Antigen-specific secretory    IgA antibodies in the gut are decreased in a mouse model of food    allergy. J Allergy Clin Immunol. 2004 August; 114(2):377-82.-   Granato D A, Piguet P F. A mouse monoclonal IgE antibody anti bovine    milk beta-lactoglobulin allows studies of allergy in the    gastrointestinal tract. Clin Exp Immunol. 1986 March; 63(3):703-10.-   Golovanov A P, Hautberge, G M, Wilson S A, Lian, L-Y. A Simple    Method for Improving Protein Solubility and Long-Term Stability. J.    Am. Chem. Soc. 2004, 126(29):8933-8939.-   Harrison M, Kilby A, Walker-Smith J A, France N E, Wood C B. Cows'    milk protein intolerance: a possible association with    gastroenteritis, lactose intolerance, and IgA deficiency. Br Med J.    1976 Jun. 19; 1(6024):1501-4.-   Harumi J. Non-IgE Mediated Food Allergy. Inflammation & Allergy—Drug    Targets, 2008, 7, 000-000.-   Jones R. M. L., Schweikart F., Frutiger S., Jaton J-C., Hughes G. J.    Thiol-disulfide redox buffers maintain a structure of immunoglobulin    A that is essential for optimal in vitro binding to secretory    component. Biochimica et Biophysica Acta 1998; 1429:265-274.-   Kelly C P, Chetham S, Keates S, Bostwick E F, Roush A M,    Castagliuolo I, LaMont J T, Pothoulakis C. Survival of    Anti-Clostridium difficile Bovine Immunoglobulin Concentrate in the    Human Gastrointestinal Tract. Antimicrob Agents Chemother. 1997    February; 41(2):236-41.-   Kohler G., Milstein C., Continuous Cultures of Fused Cells Secreting    Antibody of Predetermined Specificity, Nature 1975; 256; 495-497.-   Leibly D J, Nguyen T N, Kao L T, Hewitt S N, Barrett L K, Van    Voorhis, W C. Stabilizing Additives Added during Cell Lysis Aid in    the Solubilization of Recombinant Proteins. PLOS ONE. 2012 December;    7 (12): e52482: 1-12.-   Levy M, Kolodziejczyk A A, Thaiss C A, Elinav E. Dysbiosis and the    immune system. Nat Rev Immunol. 2017 April; 17(4):219-232. doi:    10.1038/nri.2017.7. Epub 2017 Mar. 6.-   Lullau E., Heyse S., Vogel H., Marison I., von Stockar U.,    Kraehanbuhl J-P., Corthesy B., Antigen Binding Properties of    Purified Immunoglulin A Antibodies, J. Biol. Chem. 1996;    271:16300-16309.-   Nakajima A1, Vogelzang A, Maruya M, Miyajima M, Murata M1, Son A,    Kuwahara T, Tsuruyama T, Yamada S, Matsuura M5, Nakase H, Peterson D    A, Fagarasan S, Suzuki K IgA regulates the composition and metabolic    function of gut microbiota by promoting symbiosis between bacteria.    J Exp Med. 2018 Aug. 6; 215(8):2019-2034. doi: 10.1084/jem.20180427.    Epub 2018 Jul. 24.-   Oncley J. L., Melin M., Richert D. A., Cameron J. W., Gross P. M.,    Jr., The Separation of the Antibodies, Isoagglutinins, Prothrombin,    Plasminogen and β1-Lipoprotein into Subfractions of Human Plasma. J.    Am. Chem. Soc. 1949; 71:541-550.-   Possin M E, Morgan S, DaSilva D F, Tisler C, Pappas T E, Roberg K A,    Anderson E, Evans M D, Gangnon R, Lemanske R F, Gern J E. The    relationships among immunoglobulin levels, allergic sensitization,    and viral respiratory illnesses in early childhood. Pediatr Allergy    Immunol 2010: 21: 990-996.-   Schwarze J, Cieslewicz G, Joetham A, L Sun L K, Sun W N, Chang T W,    Hamelmann E, W. Gelfand E W. Antigen-specific Immunoglobulin-A    Prevents Increased Airway Responsiveness and Lung Eosinophilia after    Airway Challenge in Sensitized Mice. Am J Resp Crit Care Med 1998;    158:519-525.-   Shimoda M, Inoue Y, Azuma N, Kanno C. Local antibody response in    Peyer's patches to the orally administered dietary protein antigen.    Biosci Biotechnol Biochem. 1999 December; 63(12):2123-9.-   Strong L. E., Blood Fractionation, pp. 576-602 in vol. 3,    Kirk-Othmer Encyclopedia of Chemical Technology. Second    Edition, H. F. Mark, J. J. McKetta, D. F. Othmer (eds), Interscience    Publishers, N Y 1963, pp. 576-602.-   Symersky J., Novak J., McPherson D. T., DeLucas L., Mestecky J.    Expression of the recombinant human immunoglobulin J chain in    Escherichia coli. Mol. Immunol. 2000; 37:133-140.-   Trajkovski V, Ajdinski L, Spiroski M. Plasma concentration of    immunoglobulin classes and subclasses in children with autism in the    Republic of Macedonia: retrospective study. Croat Med J. 2004    December; 45(6):746-9.-   Vighi G, Marcucci F, Sensi L, G. Di Cara G, Frati F. Allergy and the    gastrointestinal system. Clinical and Experimental Immunology, 153    (Suppl. 1): 3-6,2008.-   Vojdani A. Detection of IgE, IgG, IgA and IgM antibodies against raw    and processed food antigens. Nutr Metab (Lond). 2009 May 12; 6:22-   Walker A M, Kemp A S, Hill D J, Shelton M J. Features of transient    hypogammaglobulinaemia in infants screened for immunological    abnormalities. Arch Dis Child. 1994 March; 70(3): 183-186.-   Wang M, Takeda K, Shiraishi Y, Okamoto M, Dakhama A, Joetham A,    Gelfand E W. Peanut-induced intestinal allergy is mediated through a    mast cell-IgE-FcepsilonRI-IL-13 pathway. J Allergy Clin Immunol.    2010 August; 126(2):306-16, 316.e1-12.-   Yang P-C, Wang C-S, An Z-Y. A murine model of ulcerative colitis:    induced with sinusitis-derived superantigen and food allergen. BMC    Gastroenterology 2005, 5:6.-   Yoon M Y, Yoon S S. Disruption of the Gut Ecosystem by Antibiotics.    Yonsei Medical Journal (2018), 59 (1): 4

Patent applications and publications mentioned in the specification areindicative of the levels of those skilled in the art to which theinvention pertains. These applications and publications are incorporatedherein by reference to the same extent as if each individual applicationor publication was specifically and individually incorporated herein byreference.

The foregoing description is illustrative of particular embodiments ofthe invention, but is not meant to be a limitation upon the practicethereof. The following claims, including all equivalents thereof, areintended to define the scope of the invention.

1. A process for inhibiting symptoms of intestinal dysbiosis in asubject comprising: administering orally to the subject suffering fromfood allergy a purified IgA or a purified IgM; and allowing sufficienttime for said IgA or IgM to inhibit symptoms of intestinal dysbiosis inthat subject.
 2. A process for treating of intestinal dysbiosis in asubject comprising: administering orally to the subject suffering fromfood allergy a purified IgA or a purified IgM.
 3. The process of claim 1wherein said IgA or IgM is administered and is polyclonal or monoclonal.4. The process of claim 1 wherein said IgA is dimeric or polymeric 5.The process of claim 1 wherein said IgM is pentameric.
 6. The process ofclaim 1 wherein said IgA or IgM is recombinant.
 7. The process of claim1 wherein said IgA or IgM is bound to recombinant human secretorycomponent.
 8. The process of claim 1 wherein said IgA or IgM isadministered as a tablet or a capsule.
 9. The process of claim 6 whereinsaid tablet or said capsule is enterically coated.
 10. The process ofclaim 1, further comprising microencapsulating said IgA or IgM prior tosaid administration.
 11. The process of claim 1 wherein intestinaldysbiosis exacerbates IgA deficiency.
 12. The process of claim 1 whereinintestinal dysbiosis causes or exacerbates irritable bowel syndrome. 13.The process of claim 1 wherein said IgA or said IgM is stabilized by theaddition of human serum ablumin.
 14. The process of claim 1 wherein saidIgA or said IgM is stabilized by delivery with an antacid.